SUMMARY Huntington's disease (HD) is an inherited neurodegenerative disorder caused by the expansion of a CAG repeat sequence in the huntingtin (Htt) gene, leading to an abnormally long polyglutamine (polyQ) expansion in the Htt protein. The disease is characterized by selective neurodegeneration in the striatum and, to a lesser degree, the cortex. There is general consensus that three abnormalities make major contributions to neurodegeneration in HD ? transcriptional dysregulation, mitochondrial dysfunction and excitotoxicity. The focus of our previously funded R01 application was on histone deacetylase-3 (HDAC3), a transcriptional co- repressor, which we proposed plays an important role in HD pathogenesis. Strong support for a central role for HDAC3 has come from research done in our own lab using cell culture models and by others using HDAC3- selective inhibitors in HD mouse models. Our goal for the next 5 years is to gain a better understanding of the molecular mechanisms underlying HDAC3-mediated neurodegeneration in HD with the long-term objective of identifying molecules that can be targeted for therapy. We will test the novel hypothesis that MeCP2, a protein that binds methylated DNA, is an essential contributor to HDAC3 neurotoxicity. We propose that HDAC3 and MeCP2 are brought together by nuclear co-repressor, NCoR1 (nuclear corepressor 1) and/or its paralog SMRT (silencing mediator of retinoid and thyroid receptor) to form a neurotoxic protein complex that is recruited to chromatin. We propose that important targets of this HDAC3-NCoR1/SMRT-MeCP2 neurotoxic repressor complex are the genes encoding BDNF, a neurotrophic factor for cortical and striatal neurons, and peroxisome proliferator activated receptor?? (PPAR?), a nuclear receptor that plays a central role in mitochondrial biogenesis, respiration and energy metabolism. We will also test the hypothesis that an upregulation of GFAP in astrocytes and of Tau in neurons resulting from an increased expression of MeCP2 in these cell types, contributes to neurodegeneration in HD. The four specific goals of our proposal are to ? (1) Confirm the requirement for HDAC3 in HD-related neurodegeneration in mice, (2) Investigate the role of MeCP2 in HD pathogenesis. (3) Investigate the role of NcoR1/ SMRT in HDAC3 and mut-Htt-mediated neurodegeneration (4) Investigate the contribution of HDAC3 and MeCP2 in the loss of PPAR? activity in HD. (5) Investigate the contribution of GFAP and Tau in HD pathogenesis.